Women bear the greatest burden of new HIV infections throughout the world. Nevertheless, our understanding of the biology underlying HIV transmission and pathogenesis in women is incomplete. The overarching goal of this PO1 proposal is to unite a dynamic research team with complementary expertise that bridges HIV molecular biology, reproductive biology, immunology, and clinical and epidemiological research to address important, unanswered questions. 1) What sites in the female reproductive tract are most involved in HIV transmission? 2) What HIV properties and host factors critically affect transmission rates? 3) How do endogenous or exogenous sex hormones impact transmission frequency and do these factors modulate innate and adaptive immune responses in the female reproductive tract that counter infection? 4) Why have all tested vaginal microbicides not only failed to stop but often caused paradoxical increases in HIV infection? 5) Can the safety of new microbicide candidates be better assessed before large scale clinical testing? We hypothesize that 1) the upper female reproductive tract represents a highly permissive but understudied portal for HIV infection, 2) specific viral (Env) and host (semen peptides) factors importantly influence the success of male-to-female HIV transmission, 3) changes in sex hormone levels (progestin-only contraception) enhance HIV transmission and menopause adversely modulates both mucosal and systemic innate and adaptive immune responses to HIV, and 4) ineffective and unsafe microbicides activate common patterns of gene expression in the upper female reproductive tract, creating a cellular milieu that favors HIV transmission. Identification of these genes will permit construction of a predictive genetic signature for microbicide harm. These hypotheses will be tested in three specific aims involving extensive cross-project collaborations. Specific Aim 1: To study viral and host factors regulating male-to-female transmission of HIV in the female upper genital tract (Warner Greene, MD, PhD); Specific Aim 2: To explore the upper female reproductive tract as a portal of HIV transmission and to assess effects of sex steroids and microbicides on these tissues (Linda Giudice, MD, PhD, and Karen Smith-McCune, MD, PhD, and Specific Aim 3: To investigate immunopathogenesis of HIV in the female reproductive tract (Barbara Shacklett, PhD). These studies will be enabled by two essential cores, the Clinical and Data Core (Ruth Greenblatt, MD) and the Administrative Core (Drs. Greene and Greenblatt). RELEVANCE: Together, these studies promise to greatly extend our understanding of the molecular, cellular, and immunological basis for HIV transmission and pathogenesis in women. This work could also propel future efforts aimed at developing effective biomedical approaches to interdict male-to-female transmission of HIV.